Figure 9.

Schematic representation of the role of MSK1 in neuronal adaptation in response to cocaine. Both dopamine D₁ and glutamate NMDA receptors are involved in cocaine-induced ERK activation and immediate-early gene regulation (Valjent et al., 2000, 2005). D₁ receptor stimulation increases intracellular levels of cAMP, which activates PKA. NMDA receptor stimulation causes increases in intracellular calcium (Ca²⁺) levels. Both events converge on the MEK/ERK signaling cascade (P-MEK and P-ERK). Phosphorylated ERKs (P-ERKs) translocate to the nucleus, where they phosphorylate MSK1 (P-MSK1), which controls gene expression via its dual (P-MEK and P-ERK) role on histone H3 and CREB phosphorylation. (1) Histone H3 phosphorylation (P-H3) by MSK1 leads to chromatin remodeling, facilitating DNA accessibility. (2) Phosphorylation of CREB (P-CREB) by MSK1 induces transcription of the immediate-early genes c-fos or preprodynorphin (Dyn) by RNA polymerase II (Pol II).